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Metal-free hydroxylation of tertiary ketones under intensified and scalable continuous flow conditions

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Abstract

An intensified and scalable continuous flow process is presented for the hydroxylation of enolizable tertiary ketones. The procedure relies on molecular oxygen, metal-free conditions and a low toxicity solvent (DMSO). The reaction is optimized on the microfluidic scale with a model ketone substrate (isobutyrophenone) and next extended to a small library of structurally diverse enolizable ketones. High conversion and selectivity are achieved under extremely short residence time. A DFT computational study provides insights on the mechanism and selectivity on various substrates. The scalability of the hydroxylation step is next assessed in a commercial pilot scale continuous flow SiC reactor, hence providing up to 12.5 kg per day of industrially relevant α-ketols with applications ranging from Type I radical photoinitiators to intermediates for the preparation of active pharmaceutical ingredients.

Details of the Corning® Advanced-Flow™ G1 SiC reactor (Courtesy of Corning®) utilized for the intensified continuous flow hydroxylation of tertiary ketones with molecular oxygen.

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Acknowledgments

This work was supported by the F.R.S.-FNRS (Fonds National de la Recherche Scientifique, Belgium), the F.R.I.A.-FNRS (Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture, Belgium) and the University of Liège (Welcome Grant WG-13/03, JCMM). VEHK and TT are F.R.I.A.-FNRS PhD student fellows. Computational resources were provided by the “Consortium des Équipements de Calcul Intensif” (CÉCI), funded by the “Fonds de la Recherche Scientifique de Belgique” (F.R.S.-FNRS) under Grant No. 2.5020.11. François Toussaint worked on the preliminary stage of this project within the frame of his Master thesis.

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Authors and Affiliations

  1. Center for Integrated Technology and Organic Synthesis, MolSys Research Unit, University of Liège, Sart Tilman, B-4000, Liège, Belgium

    Victor-Emmanuel H. Kassin, Thomas Toupy, Guillaume Petit, Pauline Bianchi & Jean-Christophe M. Monbaliu

  2. Alysophil SAS, Bio Parc, 850 bd Sébastien Brant, 67405, Illkirch Cedex, France

    Elena Salvadeo

Authors
  1. Victor-Emmanuel H. Kassin
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  2. Thomas Toupy
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  3. Guillaume Petit
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  4. Pauline Bianchi
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  5. Elena Salvadeo
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  6. Jean-Christophe M. Monbaliu
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Correspondence to Jean-Christophe M. Monbaliu.

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Highlights

Development of a hydroxylation process for enolizable tertiary ketones that relies on metal-free conditions and molecular oxygen.

Identification of the critical process parameters that affect conversion and selectivity through DFT computations.

Intensification of the hydroxylation conditions under scalable conditions using a commercial pilot scale SiC mesofluidic reactor.

Preparation of industrially relevant α-ketols and illustration of a potential application for the photogeneration of radicals and the preparation of gold nanoparticles.

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Kassin, VE.H., Toupy, T., Petit, G. et al. Metal-free hydroxylation of tertiary ketones under intensified and scalable continuous flow conditions. J Flow Chem 10, 167–179 (2020). https://doi.org/10.1007/s41981-019-00073-6

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  • DOI: https://doi.org/10.1007/s41981-019-00073-6

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